ProjectSummary Orofacial pain is excruciating. Indeed, trigeminal neuralgia, a severe form of orofacial pain, has been termed ?suicide disease? for reasons that need no explanation. The important platinum-based chemotherapeutic, oxaliplatin (Eloxatin), commonly prescribed for colorectal cancer, produces serious off-target sensory neuropathies that include orofacial pain, cold allodynia, and abnormal oral sensations. These side effects can make it difficult for a cancer patient to consume food and beverages and can lead to drug intolerance and non- compliance. Not only is the patient her/himself deeply affected and depressed by these side-effects, but equally important, care-givers become entangled with special meal-preparations, food requirements, and general oversight. In short, chemotherapy-induced orofacial pain and oral sensory disturbances are serious problems. Finding remedies for these sensory neuropathies is paramount. Hyperalgesia and allodynia, including chemotherapy-induced neurotoxicity, have long been attributed to heightened sensitivity of sensory afferent fibers and/or sensitization of dorsal horn neurons. However, an innovative explanation has recently been postulated: allodynia and hyperalgesia are caused by abnormal coupling between sensory ganglion cells, mediated by reactive satellite glial cells. Specifically, the anti-cancer drug oxaliplatin is hypothesized to increase gap junction communication among satellite glia and generate pathological neuron-to-glia-to-neuron interactions, i.e. neural coupling within sensory ganglia. This groundbreaking hypothesis is founded mainly on compelling data from in vitro studies. If validated in vivo, this new understanding of neuropathic pain is particularly exciting because sensory ganglia lie outside the blood brain barrier. They are readily accessible to i.v. administration of therapeutic drugs. The present proposal outlines key in vivo tests of the above hypothesis regarding abnormal neuronal coupling in the trigeminal ganglion due to off-target side effects of cancer chemotherapy, particularly oxaliplatin-induced cold allodynia. We will use a recently-developed mouse model of oxaliplatin therapy combined with a new method for imaging sensory ganglion cell activity in living mice. We propose to record responses of trigeminal ganglion sensory neurons that innervate the oral cavity before and after oxaliplatin treatments that mimic chemotherapy in humans. We will use scanning laser confocal Ca2+ imaging in genetically-engineered mice in which sensory neurons express the Ca2+-sensitive reporter GCaMP. We will test for orosensory hyperalgesia such as cold allodynia after oxaliplatin treatment and for the development of neuronal crosstalk within the trigeminal ganglion that might underlie such hypersensitivity. Importantly, findings from this study may have general implications for understanding allodynia and hypersensitivity beyond orofacial pain.